Stabilization of Sur8 via PKCα/δ degradation promotes transformation and migration of colorectal cancer cells.

Kug Hwa Lee,Woo-Jeong Jeong,Do Sik Min,Sang-Kyu Lee,Pu-Hyeon Cha,Kang-Yell Choi

doi:10.18632/oncotarget.23313

Kug Hwa Lee, Woo-Jeong Jeong + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.23313

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Journal: Oncotarget	Publication Date: Dec 14, 2017
Citations: 5	License type: cc-by

Affiliation: Yonsei University, Pusan National University

Abstract

Scaffold proteins of the mitogen activated protein kinase (MAPK) pathway recruit protein kinase cascades to confer context-specificity to cellular signaling. Varying concentrations of scaffold proteins determine different aspects of signaling outputs. However, regulatory mechanisms of scaffold proteins are poorly understood. Sur8, a scaffold protein in the Ras-MAPK pathway, is known to be involved in cell transformation and migration, and is increased in human colorectal cancer (CRC) patient tissue. Here we determine that regulation of Sur8 stability mediates transformation and migration of CRC cells. Fibroblast growth factor 2 (FGF2) is identified as an external regulator that stabilizes Sur8. Protein kinase C-alpha and -delta (PKCα/δ) are also identified as specific mediators of FGF2 regulation of Sur8 stability. PKCα/δ phosphorylate Sur8 at Thr-71 and Ser-297, respectively. This phosphorylation is essential for polyubiquitin-dependent degradation of Sur8. Sur8 mutations, which mimic phosphorylation by PKCα/δ and destabilized Sur8, suppress the FGF2-induced transformation and migration of CRC cells. The clinical relevance of Sur8 regulation by PKCα/δ is indicated by the inverse relationship between PKCα/δ and Sur8 expression in human CRC patient tissues. Overall, our findings demonstrate for the first time a regulatory mechanism of Sur8 stability involving cellular transformation and migration in CRC.

Highlights

Scaffold proteins are key regulators of cellular signaling pathways, which coordinate protein kinase cascades for proper and efficient signal transduction [1,2,3]
This study provides a novel mechanism for Suppressor of Ras-8 (Sur8) stabilization by Fibroblast growth factor 2 (FGF2) signaling resulting in transformation and migration of colorectal cancer (CRC) cells
To identify a physiological signaling factor controlling Sur8, we tested the effects of several growth factors on Sur8 levels in human embryonic kidney 293 (HEK293) cells

Summary

Introduction

Scaffold proteins are key regulators of cellular signaling pathways, which coordinate protein kinase cascades for proper and efficient signal transduction [1,2,3]. It is recognized that regulations of scaffold proteins, especially regulating their concentrations, are crucial for the modulation of highly complex signaling networks. Various cellular states can be induced depending on the precise expression of scaffold proteins [2, 5]. Scaffold proteins require tight regulation of their expression levels to control complex physiological events. The MAPK pathway which includes extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38, plays important roles in controlling cellular physiologies [6]. The Ras-ERK pathway has been implicated in fundamental cellular processes including cell growth, survival, and migration [7, 8]. Scaffold proteins in the Ras-ERK pathway function to modulate signaling intensity and duration in order to produce different cellular behaviors

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